Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.

Characterisation of the Serum Metabolic Signature of Cholangiocarcinoma in a United Kingdom Cohort.

BACKGROUND: A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. METHODS: Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. RESULTS: The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. CONCLUSION: The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.

The Plasma and Serum Metabotyping of Hepatocellular Carcinoma in a Nigerian and Egyptian Cohort using Proton Nuclear Magnetic Resonance Spectroscopy.

BACKGROUND/AIMS: Previous studies have observed disturbances in the 1H nuclear magnetic resonance (NMR) blood spectral profiles in malignancy. No study has metabotyped serum or plasma of hepatocellular carcinoma (HCC) patients from two diverse populations. We aimed to delineate the HCC patient metabotype from Nigeria (mostly hepatitis B virus infected) and Egypt (mostly hepatitis C virus infected) to explore lipid and energy metabolite alterations that may be independent of disease aetiology, diet and environment. METHODS: Patients with HCC (53) and cirrhosis (26) and healthy volunteers (19) were recruited from Nigeria and Egypt. Participants provided serum or plasma samples, which were analysed using 600 MHz 1H NMR spectroscopy with nuclear Overhauser enhancement spectroscopy pulse sequences. Median group spectra comparison and multivariate analysis were performed to identify regions of difference. RESULTS: Significant differences between HCC patients and healthy volunteers were detected in levels of low density lipoprotein (P = 0.002), very low density lipoprotein (P < 0.001) and lactate (P = 0.03). N-acetylglycoproteins levels in HCC patients were significantly different from both healthy controls and cirrhosis patients (P < 0.001 and 0.001). CONCLUSION: Metabotype differences were present, pointing to disturbed lipid metabolism and a switch from glycolysis to alternative energy metabolites with malignancy, which supports the Warburg hypothesis of tumour metabolism.

Urinary metabolic profiling by 1H NMR spectroscopy in patients with cirrhosis may discriminate overt but not covert hepatic encephalopathy.

To date urinary metabolic profiling has been applied to define a specific metabolic fingerprint of hepatocellular carcinoma on a background of cirrhosis. Its utility for the stratification of other complications of cirrhosis, such as hepatic encephalopathy (HE), remains to be established. Urinary proton nuclear magnetic resonance (1H-NMR) spectra were acquired and NMR data from 52 patients with cirrhosis (35 male; 17 female, median (range) age [60 (18-81) years]) and 17 controls were compared. A sub-set of 45 patients (33 male; 12 female, [60 (18-90) years, median model for end stage liver disease (MELD) score 11 (7-27)]) were fully characterised by West-Haven criteria, Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalogram (EEG), and defined as overt HE (OHE, n = 21), covert HE (cHE, n = 7) or no HE (n = 17). Urinary proton nuclear magnetic resonance (1H-NMR) spectra were analysed by partial-least-squares discriminant analysis (PLS-DA). The results showed good discrimination between patients with cirrhosis (n = 52) and healthy controls (n = 17) (R2X = 0.66, R2Y = 0.47, Q2Y = 0.31, sensitivity-60 %, specificity-100 %) as the cirrhosis group had higher 1-methylnicotinamide with lower hippurate, acetate, phenylacetylglycine and N-methyl nicotinic acid levels. While patients with OHE could be discriminated from those with no HE, with higher histidine, citrate and creatinine levels, the best models lack robust validity (R2X = 0.65, R2Y = 0.48, Q2Y = 0.12, sensitivity-100 %, specificity-64 %) with the sample size used. Urinary 1H-NMR metabolic profiling did not discriminate patients with cHE from those without HE, nor discriminate subjects on the basis of PHES/EEG result or MELD score. In conclusion, patients with cirrhosis showed different urinary 1H-NMR metabolic profiles compared to healthy controls and those with OHE may be distinguished from those with no HE although larger studies are required. However, urinary 1H-NMR metabolic profiling did not discriminate patients with differing grades of HE or according to severity of underlying liver disease.

A longitudinal study of patients with cirrhosis treated with L-ornithine L-aspartate, examined with magnetization transfer, diffusion-weighted imaging and magnetic resonance spectroscopy.

The presence of overt hepatic encephalopathy (HE) is associated with structural, metabolic and functional changes in the brain discernible by use of a variety of magnetic resonance (MR) techniques. The changes in patients with minimal HE are less well documented. Twenty-two patients with well-compensated cirrhosis, seven of whom had minimal HE, were examined with cerebral 3 Tesla MR techniques, including T1- and T2-weighted, magnetization transfer and diffusion-weighted imaging and proton magnetic resonance spectroscopy sequences. Studies were repeated after a 4-week course of oral L-ornithine L-aspartate (LOLA). Results were compared with data obtained from 22 aged-matched healthy controls. There was no difference in mean total brain volume between patients and controls at baseline. Mean cerebral magnetization transfer ratios were significantly reduced in the globus pallidus and thalamus in the patients with cirrhosis irrespective of neuropsychiatric status; the mean ratio was significantly reduced in the frontal white matter in patients with minimal HE compared with healthy controls but not when compared with their unimpaired counterparts. There were no significant differences in either the median apparent diffusion coefficients or the mean fractional anisotropy, calculated from the diffusion-weighted imaging, or in the mean basal ganglia metabolite ratios between patients and controls. Psychometric performance improved in 50 % of patients with minimal HE following LOLA, but no significant changes were observed in brain volumes, cerebral magnetization transfer ratios, the diffusion weighted imaging variables or the cerebral metabolite ratios. MR variables, as applied in this study, do not identify patients with minimal HE, nor do they reflect changes in psychometric performance following LOLA.

Hepatic steatosis and fibrosis: Non-invasive assessment.

Chronic liver disease is a major cause of morbidity and mortality worldwide and usually develops over many years, as a result of chronic inflammation and scarring, resulting in end-stage liver disease and its complications. The progression of disease is characterised by ongoing inflammation and consequent fibrosis, although hepatic steatosis is increasingly being recognised as an important pathological feature of disease, rather than being simply an innocent bystander. However, the current gold standard method of quantifying and staging liver disease, histological analysis by liver biopsy, has several limitations and can have associated morbidity and even mortality. Therefore, there is a clear need for safe and non-invasive assessment modalities to determine hepatic steatosis, inflammation and fibrosis. This review covers key mechanisms and the importance of fibrosis and steatosis in the progression of liver disease. We address non-invasive imaging and blood biomarker assessments that can be used as an alternative to information gained on liver biopsy.

Urinary Metabotyping of Hepatocellular Carcinoma in a UK Cohort Using Proton Nuclear Magnetic Resonance Spectroscopy.

BACKGROUND: Discriminatory metabolic profiles have been described in urinary 1H nuclear magnetic resonance (NMR) spectroscopy studies of African patients with hepatocellular carcinoma (HCC). This study aimed to assess similarities in a UK cohort, where there is a greater etiological diversity. METHODS: Urine from cirrhosis and HCC patients was analyzed using a 600 MHz 1H NMR system. Multivariate analysis and median group MR spectra comparison identified metabolite alterations between groups. Metabolite identification was achieved through literature reference and statistical total correlation spectroscopy. Diagnostic accuracy was compared to serum alpha-fetoprotein (AFP). RESULTS: Of the 52 patients recruited, 13 samples from HCC and 25 from cirrhosis patients were selected. At 200 IU mL-1, diagnostic sensitivity of AFP was 27%. Multivariate analysis of urinary spectra generated diagnostic models with a sensitivity/specificity of 53.6%/96%. p-Cresol sulfate (P = 0.04), creatinine (P = 0.03), citrate (P = 0.21) and hippurate (P = 0.52) were reduced in the HCC patients. Carnitine (P = 0.31) and formate (P = 0.44) were elevated. CONCLUSION: Diagnostic sensitivity was lower than previous African studies, but still outperformed serum AFP. Reduced creatinine, citrate and hippurate and elevated carnitine are comparable with the African studies. p-Cresol sulfate alteration is a novel finding and may indicate an altered sulfonation capacity of the liver in patients with HCC.

Changes in Liver Volume in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy.

AIM: Liver volumetric analysis has not been used to detect hepatic remodelling during antiviral therapy before. We measured liver volume (LV) changes on volumetric magnetic resonance imaging during hepatitis C antiviral therapy. METHODS: 22 biopsy-staged patients (median [range] age 45(19-65) years; 9F, 13M) with chronic hepatitis C virus infection were studied. LV was measured at the beginning, end of treatment and 6 months post-treatment using 3D T1-weighted acquisition, normalised to patient weight. Liver outlines were drawn manually on 4 mm thick image slices and LV calculated. Inter-observer agreement was analysed. Patients were also assessed longitudinally using biochemical parameters and liver stiffness using Fibroscan™. RESULTS: Sustained viral response (SVR) was achieved in 13 patients with a mean baseline LV/kg of 0.022 (SD 0.004) L/kg. At the end of treatment, the mean LV/kg was 0.025 (SD 0.004, P = 0.024 cf baseline LV/kg) and 0.026 (SD 0.004, P = 0.008 cf baseline LV/kg) 6 months post-treatment (P = 0.030 cf baseline, P = 0.004). Body weight-corrected end of treatment LV change was significantly higher in patients with SVR compared to patients not attaining SVR (P = 0.050). End of treatment LV change was correlated to initial ALT (R (2) = 0.479, P = 0.037), but not APRI, AST, viral load or liver stiffness measurements. There was a correlation of 0.89 between observers for measured slice thickness. CONCLUSIONS: LV increased during anti-viral treatment, while the body weight-corrected LV increase persisted post-antiviral therapy and was larger in patients with SVR.

Hepatocellular carcinoma: Review of disease and tumor biomarkers.

Hepatocellular carcinoma (HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.

Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival. METHODS: Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)). RESULTS: (1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC. CONCLUSION: Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.

Quantitative magnetic resonance imaging in patients with cirrhosis: a cross-sectional study.

Cerebral magnetic resonance imaging was undertaken, at 3 Tesla field strength, employing magnetization transfer (MT) and diffusion-weighted imaging (DWI) sequences, in 26 patients with well-compensated cirrhosis, free of overt hepatic encephalopathy. Results were compared to those from 18 aged-matched healthy volunteers. Cerebral magnetization transfer ratios (MTR) were reduced in the frontal white matter, caudate, putamen and globus pallidus in patients with cirrhosis, compared to healthy controls, while the apparent diffusion coefficients (ADC) on DWI were significantly increased in the genu and body of the corpus callosum. An association between previous excessive alcohol consumption and both MTR and ADCs was noted, but this association was lost when controls were exercised for the severity of liver disease and psychometric impairment on multivariate analysis. Eight (31 %) of the 26 patients had impaired psychometric performance consistent with a diagnosis of minimal hepatic encephalopathy. No statistically significant difference in regional cerebral MTRs or ADCs was found in relation to neuropsychiatric status, although there was a trend towards lower MTRs in patients with impaired psychometric performance. The alterations in MTR and ADC in the patients with functionally compensated cirrhosis are compatible with theories governing the genesis of hepatic encephalopathy, including changes in astrocyte membrane permeability, with subsequent redistribution of macromolecules.

Magnetic Resonance Imaging: Principles and Techniques: Lessons for Clinicians.

The development of magnetic resonance imaging (MRI) for use in medical investigation has provided a huge forward leap in the field of diagnosis, particularly with avoidance of exposure to potentially dangerous ionizing radiation. With decreasing costs and better availability, the use of MRI is becoming ever more pervasive throughout clinical practice. Understanding the principles underlying this imaging modality and its multiple applications can be used to appreciate the benefits and limitations of its use, further informing clinical decision-making. In this article, the principles of MRI are reviewed, with further discussion of specific clinical applications such as parallel, diffusion-weighted, and magnetization transfer imaging. MR spectroscopy is also considered, with an overview of key metabolites and how they may be interpreted. Finally, a brief view on how the use of MRI will change over the coming years is presented.

Liver and spleen transient elastography and Acoustic Radiation Force Impulse Measurements. Performance and comparison of measurements in the same area concurrently assessed for liver fibrosis by biopsy.

PURPOSE: The estimation of the degree of liver fibrosis is important for prognosis, surveillance, and treatment of chronic liver disease. Although liver biopsy is the gold standard for diagnosis, it is subject to sampling error, while ultrasound-based techniques, such as Acoustic Radiation Force Impulse (ARFI) and transient elastography, have gained popularity. However, no previous comparative study has performed these ultrasound techniques at the time of biopsy. The aim of this study was to compare the reliability of these techniques to define the severity of liver fibrosis in viral hepatitis patients. PATIENTS AND METHODS: We compared liver transient elastography and Acoustic Radiation Force Impulse measurements, performed along the intended biopsy track, with liver biopsy results in 46 viral hepatitis patients, all measured on the same morning. Fibrosis was measured by histology using the Ishak fibrosis staging. RESULTS: The relative sensitivity and specificity of different incremental cut-off values for both techniques, and the predictive ability of pairwise comparison of the 3 tests (including APRI) and of their combined use with more severe grades of histology-measured liver fibrosis, show that the single variable with greatest sensitivity and specificity is TE with a cut-off of >10.0. CONCLUSION: Transient elastography has a better performance than ARFI, which has a lower sensitivity, in the diagnosis of severe stages of fibrosis. Also ARFI of the spleen is correlated with Ishak fibrosis staging, and could be a possible additional tool for the diagnosis of liver fibrosis.

Plasma Lipid Profiling in a Rat Model of Hepatocellular Carcinoma: Potential Modulation Through Quinolone Administration.

BACKGROUND/AIMS: The primary aim of this study was to characterise the blood metabolic profile of hepatocellular carcinoma (HCC) in a rat model, and the secondary aim was to evaluate the effect of the quinolone, norfloxacin on metabolic profiles and exploring the role that gut sterilisation may have on HCC development. METHODS: HCC was induced in 10 Fischer rats by administration of intra-peritoneal diethylnitrosamine (DEN) and oral N-nitrosomorpholine. Plasma was collected upon sacrifice. Five of these rats were concomitantly administered oral norfloxacin. Six Fischer non-treated rats acted as healthy controls. Proton nuclear magnetic resonance (NMR) spectra were acquired using a 600 MHz NMR system. RESULTS: Control animals were 120 g heavier than diseased counterparts. Proton NMR spectra from diseased rats displayed significant decreases in lipoproteins, unsaturated fatty acids, acetyl-glycoprotein, acetoacetate, and glucose (P ≤ 0.001). Plasma citrate and formate levels were increased (P = 0.02). Norfloxacin appeared to abrogate this effect slightly. CONCLUSION: The spectral profiles of plasma in rats with HCC display marked changes with relation to lipid metabolism and cellular turnover. Norfloxacin appears to moderate these metabolic alterations to a small degree.

Magnetic Resonance Spectroscopy: Principles and Techniques: Lessons for Clinicians.

Magnetic resonance spectroscopy (MRS) provides a non-invasive 'window' on biochemical processes within the body. Its use is no longer restricted to the field of research, with applications in clinical practice increasingly common. MRS can be conducted at high magnetic field strengths (typically 11-14 T) on body fluids, cell extracts and tissue samples, with new developments in whole-body magnetic resonance imaging (MRI) allowing clinical MRS at the end of a standard MRI examination, obtaining functional information in addition to anatomical information. We discuss the background physics the busy clinician needs to know before considering using the technique as an investigative tool. Some potential applications of hepatic and cerebral MRS in chronic liver disease are also discussed.

PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism.

BACKGROUND & AIMS: Hepatitis C virus (HCV) associates with lipoproteins to form "lipoviral particles" (LVPs) that can facilitate viral entry into hepatocytes. Initial attachment occurs via heparan sulphate proteoglycans and low-density lipoprotein receptor (LDLR); CD81 then mediates a post-attachment event. Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels. We measured LVP and PCSK9 in patients chronically infected with HCV genotype (G)3. PCSK9 concentrations were also measured in HCV-G1 to indirectly examine the role of LDLR in LVP clearance. METHODS: HCV RNA, LVP (d<1.07g/ml) and non-LVP (d>1.07g/ml) fractions, were quantified in patients with HCV-G3 (n=39) by real time RT-PCR and LVP ratios (LVPr; LVP/(LVP+non-LVP)) were calculated. Insulin resistance (IR) was assessed using the homeostasis model assessment of IR (HOMA-IR). Plasma PCSK9 concentrations were measured by ELISA in HCV-G3 and HCV-G1 (n=51). RESULTS: In HCV-G3 LVP load correlated inversely with HDL-C (r=-0.421; p=0.008), and apoE (r=-0.428; p=0.013). The LVPr varied more than 35-fold (median 0.286; range 0.027 to 0.969); PCSK9 was the strongest negative predictor of LVPr (R(2)=16.2%; p=0.012). HOMA-IR was not associated with LVP load or LVPr. PCSK9 concentrations were significantly lower in HCV-G3 compared to HCV-G1 (p<0.001). PCSK9 did not correlate with LDL-C in HCV-G3 or G1. CONCLUSIONS: The inverse correlation of LVP with apoE in HCV-G3, compared to the reverse in HCV-G1 suggests HCV genotype-specific differences in apoE mediated viral entry. Lower PCSK9 and LDL concentrations imply upregulated LDLR activity in HCV-G3.

Reasons why West Africa continues to be a hotbed for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) exhibits a huge disease burden on West Africa, with a large proportion of all HCC cases worldwide occurring in the sub-region. The high HCC prevalence is due to the endemicity of a number of risk factors, most notably hepatitis B, C and HIV. West African HCC also displays a poor prognosis. Generally speaking, this is owing to more aggressive tumours, late patient presentation and inadequate management. Exposure to chronic viral hepatitis, more carcinogenic West African strains of hepatitis B virus and carcinogens such as aflatoxin B1 all encourage tumour growth. Lack of patient confidence in the healthcare system contributes to poor health-seeking behaviors and management of the disease can be lacking, due in part to poor health infrastructure, resources available and lack of access to expensive treatment. There is also much we do not know about West African HCC, especially the effect rising obesity and alcohol use may have on this disease in the future. Suggestions for improvement are discussed, including surveillance of high-risk groups. Although there is much to be done before West African HCC is thought to be a curable disease, many steps have been taken to move in the right direction.

Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function.

Proton pump inhibitors (PPI) have been associated with infectious complications in cirrhosis, but their impact on distal gut microbiota composition and function is unclear. We aimed to evaluate changes in stool microbiota composition and function in patients with cirrhosis and healthy controls after omeprazole therapy. Both 15 compensated cirrhotic patients and 15 age-matched controls underwent serum gastrin measurement, stool microbiota profiling with multitagged pyrosequencing, and urinary metabolic profiling with NMR spectroscopy to assess microbial cometabolites before/after a 14-day course of 40 mg/day omeprazole under constant diet conditions. Results before (pre) and after PPI were compared in both groups, compared with baseline by systems biology techniques. Adherence was >95% without changes in diet or MELD (model for end-stage liver disease) score during the study. Serum gastrin concentrations significantly increased after PPI in cirrhosis (pre 38.3 ± 35.8 vs. 115.6 ± 79.3 pg/ml P < 0.0001) and controls (pre 29.9 ± 14.5 vs. 116.0 ± 74.0 pg/ml, P = 0.001). A significant microbiota change was seen in both controls and cirrhosis after omeprazole (QIIME P < 0.0001). Relative Streptococcaceae abundance, normally abundant in saliva, significantly increased postomeprazole in controls (1 vs. 5%) and cirrhosis (0 vs. 9%) and was correlated with serum gastrin levels (r = 0.4, P = 0.005). We found significantly reduced hippurate in cirrhosis vs. controls both pre- and postomeprazole and increased lactate in both groups post vs. preomeprazole, whereas dimethylamine (DMA) decreased in cirrhosis only. On correlation network analysis, significant changes in linkages of bacteria with metabolites (hippurate/DMA/lactate) were found postomeprazole, compared with pre-PPI in cirrhosis patients. In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth.